Abstract 779: A NRF1-driven JRK-mediated β-catenin transcriptional activity contributes to the aggressive growth of ovarian cancer
Authors: Ana Ruas, Quentin Felty, Jayanta K. Das, Alok Deoraj, Changwon Yoo, Deodutta Roy
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the most lethal gynecological cancer, accounting for thousands of cancer-related deaths in the United States every year. Though there has been progress towards understanding ovarian cancer pathogenesis, much is not yet understood about the molecular mechanisms that facilitate chemoresistance and metastasis. Our work has shown that nuclear respiratory factor 1 (NRF1) is highly active in several human cancers, though the role of NRF1 remains largely unexplored in ovarian carcinomas. Therefore, our aim was to examine the role of this transcription factor in ovarian cancer, since understanding its transcriptional landscape may reveal NRF1 or its target genes as possible therapeutic targets for this highly aggressive cancer. The Cancer Genome Atlas (TCGA) was utilized to collect RNA-Seq data from 379 serous cystadenocarcinoma samples, where we found that about 20% of ovarian cancer patients had altered NRF1 expression, showing either high expression or amplification of this transcription factor. Patients with high NRF1 expression were found to have decreased survival compared to patients with low NRF1 expression. NRF1 amplification was also correlated with the overamplification of one of its target genes - Jrk helix-turn-helix protein (JRK) in 26% of the samples. JRK regulates centrosome amplification, and through the production of mitotic spindle abnormalities, centrosome amplification contributes to genomic instability. Further investigation of the relationship between NRF1 and JRK uncovered that protein levels of JRK and β-catenin were significantly higher in NRF1-induced stem-like cells compared to the control group, and JRK is known to bind to β-catenin. Our NRF1 ChIP-Seq analyses showed that promoters of these two genes - JRK and CTNNB1 - were bound to NRF1. The Flow Assorted Cell Sorting (FACS), ChIP-Seq, RNA Seq and confocal microscopic studies suggest that through JRK, NRF1 regulates β-catenin transcriptional activity. Amplified gene expression is the one of the first steps towards oncogene activation, and our findings illustrate that altered NRF1 expression (i.e., overexpression or amplification) coupled with that of JRK influences the prognosis of patients diagnosed with ovarian cancer. The Wnt/β-catenin pathway is also highly active in the aggressive ovarian cancer. In addition to JRK, through the activation of β-catenin, NRF1may also affect the development of ovarian tumors. Taken together, our findings provide a novel insight into the molecular basis of the contribution of NRF1-driven JRK-mediated β-catenin transcriptional activity to the susceptibility of highly aggressive ovarian cancer. A better understanding of how ovarian neoplasm formation depends on NRF1-JRK-β-catenin pathway may open new avenues for therapeutic strategy against ovarian cancer. Citation Format: Ana Ruas, Quentin Felty, Jayanta K. Das, Alok Deoraj, Changwon Yoo, Deodutta Roy. A NRF1-driven JRK-mediated β-catenin transcriptional activity contributes to the aggressive growth of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 779.